Homeostatic Role and Therapeutic Potential of the Neuroprotective Retinal Lipoxin Circuit

项目摘要/摘要 青光眼是一种视网膜和视神经的慢性变性，是不可逆转的主要原因。 据估计，全球有8000万人患有失明。它也是最常见的神经退行性变 全世界的疾病，影响着大约300万美国人，估计每年给美国带来29亿美元的负担 医疗保健系统。我们对病因和驱动发病的分子机制的理解 青光眼的症状仍然不完全。主要治疗方案仅限于降低眼压(IOP)。 目前还没有神经保护性疗法来预防或挽救定义青光眼的退行性级联。 星形胶质细胞是视神经头(ONH)结构和副炎性变化的中心驱动力 随后，不可逆转的视网膜神经节细胞(RGC)死亡。新出现的证据表明，星形胶质细胞 青光眼的神经保护和支持生存的活动。这些保护信号的性质和相关性 目前仍不清楚。我们最近在静息的视网膜星形胶质细胞中发现了一种分泌的神经保护活性，它 被证明是一种以前未知的视网膜脂蛋白脂类介体电路。脂氧素是一类有效的 专门化前体脂介体(SPM)，由于其独特的特性，正被开发为药物靶点 在抑制和化解其他组织的局部炎症方面起到了既定的作用。我们发现有两个 脂氧素，LXA4和LXB4，是由静息的星形胶质细胞产生的，在健康的视网膜和OHN中， 脂氧素受体在视网膜节细胞中选择性地表达，它识别了一种以前未知的直接神经活动。 脂氧素。这一内在途径在视网膜/ONH应激反应中被失调。更重要的是，我们 证实了脂氧素治疗通过增加RGC存活率和抢救而具有神经保护作用 急性神经毒性视网膜损伤模型和慢性眼压依赖性视网膜损伤模型的RGC功能 青光眼样神经变性。我们假设脂氧素回路是一个重要的旁分泌信号。 维持神经元动态平衡和保护视网膜免受压力的机制。在多元PI研究中 项目，我们将描述这一新型神经保护网络的特征，定义其作用机制，并探索 用以下三种药物放大脂氧素回路作为神经保护治疗靶点的疗效 具体目的：1)研究LXA4和LXB4在视网膜、ON和星形胶质细胞中的形成机制 健康和青光眼损伤的背景，2)定义LXA4和LXB4前体的不同作用机制。 视网膜节细胞中的生存信号，以及3)研究扩大脂氧素回路以预防 和/或阻止RGC退化。这个项目的目标是对一部小说产生变革性的见解 神经支持机制及其在损伤或应激后的失调。最重要的是，我们将测试 这种保护电路的放大可以防止或阻止视网膜/视神经退化和视力丧失。

Project Summary/Abstract Glaucoma is a chronic degeneration of the retina and optic nerve, and a leading cause of irreversible blindness, estimated to afflict 80 million people worldwide. It is also the most common neurodegenerative disease in the world, affecting ~3 million Americans with an estimated $2.9 billion annual burden to the US Health Care system. Our understanding of the etiology and molecular mechanisms that drive the pathogenesis of glaucoma remain incomplete. Primary treatment options are limited to lowering intraocular pressure (IOP). There are no neuroprotective therapies to prevent or rescue the degenerative cascades that define glaucoma. Astrocytes are a central driver of structural and parainflammatory changes at the optic nerve head (ONH) and subsequent, irreversible retinal ganglion cells (RGC) death. Emerging evidence indicates that astrocytes have neuroprotective and pro-survival activities in glaucoma. The nature and relevance of these protective signals remains unclear. We recently identified a secreted neuroprotective activity in resting retinal astrocytes, which proved to be a previously unknown resident retinal lipoxin lipid mediator circuit. Lipoxins are a family of potent specialized proresolving lipid mediators (SPMs), which are being developed as drug targets due to their established role in dampening and resolving local inflammation in other tissues. We discovered that two lipoxins, LXA4 and LXB4, are generated by resting astrocytes and in the healthy retina and OHN and that a lipoxin receptor is selectively expressed in RGCs, which identified a previously unknown direct neural activity of lipoxins. This intrinsic pathway is dysregulated in response to retinal/ONH stress. More importantly, we established that therapeutic treatment with lipoxins is neuroprotective by increasing RGC survival and rescuing RGC function in both an acute neurotoxic retinal injury model, and a chronic IOP dependent model of glaucoma like neurodegeneration. We hypothesize that the lipoxin circuit is an important paracrine signaling mechanism to maintain neuronal homeostasis and protect the retina against stress. In a multiple-PI Research Project, we will characterize this novel neuroprotective network, define its mechanism of action and explore the efficacy of amplifying the lipoxin circuit as a therapeutic target for neuroprotection with the following three specific aims: 1) Characterize the mechanism of LXA4 and LXB4 formation in retina, ON, and astrocytes in the context of health and glaucomatous injury, 2) Define the distinct mechanisms of action for LXA4 and LXB4 pro- survival signaling in RGCs, and 3) Investigate the therapeutic potential of amplifying lipoxin circuits to prevent and/or stop RGC degeneration. This goal of this project is to generate transformative insights into a novel neuronal support mechanism and its dysregulation following injury or stress. Most importantly, we will test if amplification of this protective circuit can prevent or stop retinal/optic nerve degeneration and vision loss.